Vaccines: Types, Mechanisms and Uses

 The term “vaccine” refers to a preparation of live
(usually attenuated) or inactivated organisms or
their antigenic constituents which have been
formulated to stimulate specific immunity.
 Vaccination is the administration of antigenic
material (the vaccine) to produce immunity to
a disease.

 The term vaccine derives from Edward Jenner's
1796 use of the term cowpox (Latin variolæ
vaccinæ, adapted from the Latin vaccīn-us, from
vacca cow), which, when administered to
humans, provided them protection against small
pox.

 1796 –Edward Jenner – cowpox vaccine
 1885 – Lois Pasteur-rabies vaccine
 19th century - national prestige-laws were passed
 20th century - introduction of several successful
vaccines, including those against diphtheria,
measles, mumps & rubella
 the polio vaccine in the 1950s and the eradication
of smallpox during the 1960s and 1970s

Immunity
Innate
(skin, mucucs membrane, phagocytes)
Acquired
natural Artificial
Active passive Active
passive
Antigens or pathogens
entering naturally
Immune response
Antibodies
(placental or colostrum)
Antigen introduction
(vaccines)
Performed
antibodies (Ig)

vaccines
Live
attenu
ated
Killed
Toxoi
d
Subu
nit
Conju
gate
experimental
Reco
mbina
nt
DNA-
vacci
nes
T-cell
recept
or
Valence
Mono
valent
polyva
lent

 live, attenuated microorganisms - live micro-
organisms cultivated under conditions that
disable their virulent properties, or
 which use closely-related but less dangerous
organisms to produce a broad immune response
 Provoke more durable immunological responses
& are preferred type for healthy adults.
 Eg. yellow fever, measles, rubella, mumps etc.

 killed microorganisms - previously virulent
micro-organisms --killed with chemicals or heat.
 Eg.vaccines against flu, cholera, bubonic plaque,
polio and hepatitis A

 Inactivated toxic compounds in cases where
these (rather than the micro-organism itself)
cause illness.
 Eg. Tetanus and diphtheria

 Rather than introducing an inactivated or
attenuated micro-organism, a fragment of it can
create an immune response.
 Eg. Hepatitis B vaccines -composed of only the
surface proteins of the virus (produced in yeast)
and the virus-like particle (VLP) vaccine against
human papillomavirus (HPV) that is composed
of the viral major capsid protein.

 certain bacteria have polysaccharide outer coats
that are poorly immunogenic-by linking these
outer coats to proteins (e.g. toxins), the immune
system can be led to recognize the
polysaccharide as if it were a protein antigen.
 Eg. Haemophilus influenzae type B vaccine.

 Recombinant Vector - by combining the
physiology of one micro-organism and the DNA
of the other, immunity can be created against
diseases that have complex infection processes

 DNA vaccination - It works by insertion (and
expression, triggering immune system
recognition) into human or animal cells, of viral
or bacterial DNA.
 Immune system recognize the proteins expressed
-mount an attack against these proteins & cells
expressing them.
 These cells live for a very long time--pathogen
that normally expresses these proteins
encountered -- attacked instantly by the immune
system.

 T-cell receptor peptide vaccines are under
development for several diseases using models of
Valley Fever, stomatitis, and atopic dermatitis.
These peptides have been shown to modulate
cytokine production and improve cell mediated
immunity.

1st generation Vaccines contain whole
organsims
Killed or attenuated eg.
Antityphoid, cholera,
sabin, salk
Killed or attenuated non-
pathogen closely related to
pathogen eg. BW &
smallpox vaccines
2nd generation Vaccines containing only
the immunogenic subunit
Theses vaccines are free
from side effects of whole
organsim vaccines
3rd generation Vaccines are biosynthezed
using recombinant DNA
technology
Specific genes, responsible
for antigenic activity, are
isolated from pathogens.
These can be combined
with genes from other
organsims. Eg. Vaccina
virus

 Suspending fluid
 Preservatives, stabilizers, antibiotics
 Adjuvants

molecular weight
 Immunogenicity increases with molecular weight
 Substances < 5kda rarely immunogenic

Chemical complexity
 Immunogenicity increases with chemical
complexity
 Globular proteins are more immunogenic than
polysaccharides

Foreignness
 More dissimilar , more immunogenic
 Haptens + carrier molecule = immunogenic

 dirty little secret of vaccines
 Bind vaccine components & release them slowly
= maintain continuous stimulation
 Enhance immune response to an antigen
 Aluminum compounds, oil emulsions, plant
products, bacterial products, biopolymers &
natural immunomodulators such as cytokines
 Only adjuvants currently approved for human use
are aluminum compounds

 Muramyl dipeptide derived adjuvants
 Lipopolysacchride, lipid A and monophosphoryl,
lipid A adjuvants
 Saponin, quil A and QS21 adjuvants

 French microbiologist Albert Calmette &
veterinary surgeon Camille Guerin
 231 s/c of M bovis over 13years
 Only effective vaccine against tuberculosis
 Copenhagen (Danish 1331) & Pasteur
 Efficacy 50-80% for miliary & meningeal form
and 50% for pulmonary form of disease

• Contains 0.1-0.4million live viable bacilli per
dose
• Supplied as lyophilized preparation in multi –
dose dark colored ampoules or 2ml vials with
NS as diluent
• Lyophilized form can be stored at 2 ° -8 °C x
12 months
• Reconstituted vaccine stored at 2 ° -8 °C,
protected from light & used within 4-6hrs
• Recommended dose is 0.1ml or 0.05ml as
suggested by manufacturer

 Injection strictly intradermal, with tuberculin
syringe & 26G/27G needle on convex part of
deltoid after cleaning with sterile saline
 5mm wheal=successful I/D administration
 Injection site--»no visible change for several
days--»papule in 2-3 weeks--»increase to 4-8mm
by end of 5-6 weeks--»heals with ulceration--
»scar after 6-12 weeks
 No Rx requirement
 At birth or at 6 weeks with other vaccines
 Catch up vaccines till 5 years

 Ipsilateral LAP--»FNAC --»AFB +ve--»Rx
surgical removal & repeated aspiration
 Disseminated BCG infection in
immunocompromised
 BCG can be given any vaccine except with
MMR (a gap of 4 weeks recommended)

 DTwP vaccine
 Popularly known as triple antigen
 Composed of tetanus & diphtheria toxins +whole
cell pertussis adsorbed on insulble aluminum
salts (adjuvants)
 Content of diphtheria toxoid 20-30Lf & tetanus
5-25 Lf
 Stored at 2° -8° C, never frozen, if frozen
discarded

 Dose 0.5ml I/M anterolateral aspect of thigh
 Immunogenicity (protective titre for
diphtheria≥0.1IU/ml & for tetanus ≥0.01IU/ml )
for diphtheria/tetanus of 3 doses exceeds 95%
 Efficacy for pertussis is lower (70-90%)
 Immunity wanes over 6-12 years & boosting
requires

 Most adverse effects due to pertussis component
 Pain, swelling, redness, fever, , anorexia,
vomitings, persistent crying
 Hypotonic hypo-responsive episodes, seizers,
encephalopathy, sudden infant death are rare
 Absolute C/I to any pertussis vaccine are
anaphylaxis or encephalopathy within 7 days
 safe in stable neurological disorders

 Dose is 3 primary doses at 6,10 & 14 weeks
 2 boosters at 15-18 months and 5 years
 Early 1° immunization desirable as there is no
maternal antibody against pertussis
 Schedule for catch up vaccination--»0, 1 , 6
months
 2nd childhood booster not required if last dose
beyond 4 years
 DTwP not recommended in children aged 7 years
 Immunize those recovering--»natural infection
does not offer complete protection

 DTaP vaccine
 Due to devastating effects of pertussis in whole
cell vaccine--» acellualr vaccine developed in
Japan in 1981
 It includes pertussis toxin(PT) as essential
component with or without filamentous
hemagglutinin (FHA), pertactin(PRN) & fimbrial
hemagglutinins 1,2 & 3 (FIM)

 Currently available in India--» Tripacel™
(PT,PRN,FHA,FIM2 &3), Infantrix ™
(PT,FHA,PRN), Pentaxim ™ (PT & FHA, IPV,
Hib)
 Stored at 2° -8° C & dose is 0.5ml I/M
 Efficacy & C/I & schedule similar to whole cell
vaccine & also not recommended in children
more than 7 years
 Fewer side effects but costlier

 Antibodies to tetanus decline overtime--»
boosters required
 TT contains 5Lf (1 of most heat stable vaccines),
stored at 2° -8° C & dose is 0.5ml I/M
 In those who have completed booster vaccination
with DTwP/DTaP, TT boosters every 10 years
provide sufficient protection

 not immunized--» 2 doses 1 month apart during
pregnancy
 1st dose at time of contact & 2nd 1 month later &
at least 2 weeks before delivery
 Single dose sufficient for pregnancies in next 5
years--» 2 doses thereafter
 Those who received 5 doses in atleast 2.5 years,
protected for their reproductive years
 Those who received 3 primary doses in infancy, 2
doses during 1st pregnancy are recommended--»
1 dose in 2nd pregnancy gives lasting protection

 Those who received 3 doses + 1 booster in
childhood 1 dose each in 1st & 2nd pregnancy
provide lasting protection
 Those who received 3 primary doses +2 boosters-
-» only 1 dose in 1st pregnancy

Doses of TT in past Clean, minor wounds All other wounds
Unknown, <3 doses,
immunodeficient
TIG TT TIG TT
Yes Yes No Yes
≥3doses No No No No
Unimmunized--» 3 doses , 0,1 and 6 months

 Contains diphtheria & tetanus toxoid in similar
amount as in DTwP/DTaP
 Indicated in children <7 years where pertussis
vaccination C/I

 Diphtheria antibody levels decline overtime--»
increased susceptibility
 Contains usual tetanus toxoid+ 2 U of diphtheria
toxoid
 Replacement of DTwp/Dtap/Dt in >7years along
with Tdap in replacement of TT

 Following primary vaccination effect wanes off
in 6-12yrs--» booster
 Boostrix™ in India (TT 5+Dt 2Lf+3 acellular
pertussis components + aluminium hydroxide)
 Single dose in previously vaccinated

 6 serotypes of capsulated H. influenzae
 Type b is most important
 Conjugated vaccines
 Hib capsular polysaccharide (polyribitol phosphate)
Conjugated with a protein carrier
 Currently available Hb OC (carrier CRM197 mutant
C. diphtheria toxin protein)
 PRP-T (carrier tetanus toxoid)
 PRP OMP (carrier N meningitidis protein OM
complex)
 PRP-D withdrawn

 HbOC & PRP-T--» marginal increase in antibody
after 1st dose--»marked increase after 2nd & 3rd
dose
 PRP-OMP --» increase in antibody after 1st and
marginal after next

 Dose --» 0.5ml i/m for children<6months --» 3
doses ( at diff. of 4weeks) --» 2 doses between 6-
12 weeks --» booster at 18 weeks
 Catch up vaccination not recommended for
healthy children above 5 years
 For children>15 months --» a single dose
sufficient

 Whole cell inactivated Typhoid/Paratyphoid
vaccines (TA/TAB) --» earliest vaccines --» no
longer available
 Oral live attenuated Ty21a vaccine
 Vi conjugate typhoid vaccines

 S. typhi Ty21a is live attenuated strain with
mutation in gal E gene--» lacks enzyme UDP-gal
4 epimerase--» genetically stable, no virulence
 Protection by local gut immunity--» no biological
marker for immunity
 Bacteria acid labile--» enteric coated capsules or
liquid (not available commercially)
 Stored at 2 ° -8° C

 3 doses x alternate days on empty stomach with
cool liquid
 Not given in diarrhea
 Antimicrobials not given 3 days before & 3 days
after
 Can be administered with all other vaccines
 Protection within a week & revaccination every
3-7 years
 No adverse affects, avoided in pregnancy
 N/A in India

 Contains highly purified antigenic fraction of Vi-
capsular polysaccharide antigen of S. typhi
 Contains 25-30µg of purufied polysaccharide in
0.5ml of phenolic isotonic buffer for s/c or i/m
use
 Stored at 2°-8° C (not frozen)
 Not immunogenic below 2 years
 Biological marker anti-Vi antibodies (1µg/ml)

 No interference with WIDAL
 Dose single dose in children >2 years
 Can be given with other vaccines
 Revaccination every 3 years
 Adverse effects Pain, swelling
 C/I in h/o hypersensitivity
 Can be given in HIV

 Dose 0.5ml I/M every 3 years beginning of 2
years till 18 years
 With h/o enteric fever – vaccination after 4
weeks

 Conjugation with non-toxic recombinant P.
aeruginosa exotoxin A (Vietnam)
 Conjugation with tetanus toxoid (India)

 2 vaccines
• Unconjugated pneumococcal polysaccaride
vaccine
• Conjugate vaccine

 PPV is 23 valent vaccine
 T-Cell dependent vaccine
 Poorly immunogenic below 2 yrs of age
 Low immune memory
 Does not reduce nasopharyngeal carriage
 Does not provide HERD immunity
 70% Efficacy
 Brand name- PNEUMA 23 (Safoni Pasteur)

 Conjugated pneumococcal vaccine is a 7 valent
vaccine
 High immunogenicity
 Good Herd immunity
 95% reduction in invasive pneumococal ds
 Effective in children <2 yrs of age
 IAPCOI RECOMMENDATIONS- The conjugate
pneumococcal vaccines ideally should be available to
all children

 Congenital immunodeficiency, HIV
 Immunosuppressive therapy, Organ transplant
recipients
 Sickle cell disease, asplenia/hyposplenia
 Chronic cardiac disease
 Chronic liver disease
 Chronic renal disease
 Diabetes mellitus
 Chronic pulmonary disease excluding asthma unless
on high dose oral steroids

 IAPCOI recommends administration of both
PCV and PPV 23 in all high-risk children who
can afford the vaccine
 If PCV is not affordable, at least PPV 23
should be given to high-risk children above 2
years of age

 Healthy children (PCV vaccine)
• Dose - 0.5 ml IM
• Routine vaccination: 3 doses at 6,10,14 weeks
1 booster at 15-18 months
 Catch up vaccination:
• 6-12 months: 2 doses (4-8 weeks apart) &
1 booster at 15 -18 months
• 12-23 months: 2 doses (8 weeks apart)
• 24-59 months: single dose

High risk children
• If affordable- give PCV same schedule for
children <5 yrs and single dose for >5 yr
• Children >2 yrs PPV 23 single dose .5 ml IM
& keep 2 months gap if PCV given earlier

 It protects against 4 subtypes of meningococcus
- A, C, Y, and W-135.
 It is for persons aged 2 years and older >55yrs
who are at risk.
 Single dose- 0.5ml, Subcutaneously in mid arm.
 Booster every 3 years
 Use limited to high-risk populations(>2 years
during epidemic)
 Military recruits, travelers

 Newer conjugate vaccine links capsular
polysaccharides (A,C,Y, and W-135) to a protein
carrier (diphtheria toxoid)
 Induces immunologic memory, longer-term
immunity, long lasting protection than the
polysaccharide vaccine.
 It is licensed for use in persons 11-55 years of age.
 Single dose, 0.5ml, IM in mid arm.

 Recommended for people at increased risk of
meningococcal disease:
• Individuals with damaged or missing spleen.
• Persons with terminal complement component
deficiency
• Persons working with meningococcus bacteria in
laboratories.
• Travelers to certain countries in sub-Saharan Africa as
well to other countries for which meningococcal
vaccine is recommended.
• Anyone exposed to meningitis during an outbreak.

 If MPSV is given, an additional dose is
recommended if they remain at risk.
 If MCV is given, no additional doses are
recommended at this time, even for people who
remain at high risk.
 Brand name
Meningo A+C (Safoni pasteur)

 WC/rBS vaccine
 Consists of killed whole-cell V. cholerae O1 with
purified recombinant B-subunit of cholera toxoid
(WC/rBS).
 Safe & confers 85–90% protection during six
months in all age groups after administration of
two doses, one week apart.

 Variant WC/rBS vaccine
 A variant of the WC/rBS vaccine containing no
recombinant B-subunit
 Administered in two doses, one week apart.
 Protective efficacy of 66% at eight months in all
age groups.
 The vaccine is licensed only in Viet Nam.

 CVD 103-HgR vaccine
 Consists of an attenuated live oral genetically
modified V. cholerae O1 strain (CVD 103-HgR).
 Efficacy-it has been found that a single dose
confers high protection (95%) against V.
cholerae. Classical and 65% protection against V.
cholerae El Tor

 1st vaccine against leprosy BCG
 Killed M. leprae+BCG –phase III trial
 Gamma irradiation killed ICRC bacilli –phase III
trial
 Killed M. welchii-under trial
 M.habana—early stage of development
 Killed M. vaccae +BCG—early stage of
development
 Dilipidified cell component of M leprae- safety &
toxicity studies under progress

 Killed whole cell leptospiral vaccines available in
some countries, including Japan.
 Japanese vaccine consists of formalin-killed
leptospires.
 Concentrations & serovars are 250 million/ml each
of Australis, Autumnalis, and Hebdomadis and 500
million/ml of Copenhageni
 Administered initially using two subcutaneous
injections of 1.0 ml given at a 7-day interval.
 The booster injection is 1.0 ml of vaccine injected
subcutaneously and given within 5 years after the
second initial dose.
 Efficacy 60-100%

 used since the late 19th century reduces
incidence & severity of disease resulting from
the bite of infected fleas.
 licensed in United States prepared from Y.
pestis organisms grown in artificial media,
inactivated with formaldehyde, and preserved
in 0.5% phenol.
 The vaccine contains trace amounts of beef-
heart extract, yeast extract, agar, and
peptones and peptides of soya and casein.

 All laboratory and field personnel working with
Y. pestis
 Persons engaged in aerosol experiments with Y.
pestis
 Persons engaged in field operations in areas with
enzootic plague
 where preventing exposure is not possible (such
as some disaster areas).

 All injections should be given intramuscularly.
 Adults and children greater than or equal to 11
years old:
 Primary series --›› 3 doses of vaccine --›› 1st
dose, 1.0 ml --›› 2nd dose, 0.2 ml, 4 weeks later -
-›› 3rd dose, 0.2 ml, 6 months after 1st dose
 If an accelerated schedule is essential, 3 doses of
0.5 ml each --›› administered at least 1 week
apart

 Needed because of continuing exposure --›› 3
booster doses should be given at approximately
6-month intervals.
 Thereafter, antibody levels decline slowly and
booster doses at 1- to 2-year intervals, depending
on the degree of continuing exposure
 Recommended booster dosages for children &
adults same as 2nd & 3rd doses in the primary
series.

 general malaise, headache, fever, mild
lymphadenopathy, and erythema and induration
at the injection site in about 10% of recipients.
 occur more commonly with repeated injections
 Sterile abscesses occur rarely
 sensitivity reactions manifested by urticarial and
asthmatic phenomena have been reported.

 From avirulent strains
 Cell free filtrate containing protective antigens &
bacterial products
 Potential biowar agent
 US armed forces – 1998
 6 doses-s/c-0-2wks-4wks-6mnths-12mnths-
18mnths
 Mild local or systemic reactions
 Not available for general public

 An adverse event following immunization
(AEFI) or vaccine associated adverse event
(VAE) is defined as an unwanted, temporally
associated event following immunization that
might or might not be caused by the vaccine or
the immunization process.

 mere coincidence (eg sudden infant death
syndrome following whole cell pertussis vaccines) or
a true adverse immunization reaction.
 Adverse immunization reactions may be further
classified as
 Adverse vaccine reaction (vaccine induced)-vaccine
is causally related to the reaction; e.g. anaphylaxis.
 Trigger reaction (vaccine potentiated)--reaction
is triggered by the vaccine, e.g. febrile seizure
following vaccination in a predisposed child.

 Programmatic errors--most common cause for
serious adverse events and death following
vaccination.
Eg.Deaths following measles vaccination due to
toxic shock syndrome resulting from improper
reconstitution and storage of measles vaccine
 Injection reaction.– Eg. syncope due to pain of
vaccination, injection site abscesses, sciatic nerve
damage due to gluteal injection and transmission
of blood borne pathogens such as
HIV/HBV/HCV.

The system of transporting, storing and
distributing vaccines in a potent state at the
recommended temperature from the point of
manufacture to the point of use is the cold chain.

 Personnel responsible for vaccine distribution.
 Appropriate equipment to store and transport
vaccines.
 Appropriate transport facilities.
 Maintenance of equipment.
 Monitoring.

 The Vaccine Vial Monitor (VVM) is a time and
temperature sensitive colored label that provides
an indication of the cumulative heat to which the
vial has been exposed.
 Warns end user exposure to heat likely to have
degraded the vaccine beyond an acceptable level.
 Used especially for temperature monitoring of
OPV (most thermo labile Vaccine)
 VVM is applied to the outside of a vaccine vial

 consist of t° sensitive material--changes color
gradually on being exposed to heat—change is
irreversible
 Do not give any information on cold injury to
vaccines.

 1. Inner square is white, or lighter than outer
circle: If the expiry date has not passed, vaccine
can be used.
 2. Inner square matches color of outer circle or is
darker than outer circle: vaccine should be
discarded, regardless of expiry date.

 Viral & bacterial antigens have been produced in
transgenic plants
 Hepatitis B surface antigen,Escherichia coli
enterotoxin, & rabies virus glycoprotein
produced in transgenic plants induce IgG
antibodies with correct antigenic specificity after
oral administration to mice
 The potential low cost and the ability to effect
vaccination simply by having a person eat a
selected part of the transgenic plant.

 DNA that encodes foreign antigens can be
inserted together with a suitable promoter in a
bacterial plasmid
 I/M injection of this complex induces an immune
response to the antigen encoded by the DNA in
mice.
 Response is very strong, since bacterial DNA,
unlike vertebrate DNA, is recognized as foreign
by vertebrates

 Live-Agent Vaccines as Vectors of Other
Vaccine Antigens
 vaccines composed of attenuated viruses or
bacteria as carriers(vectors) of other antigens.
 Incorporating DNA encoding an antigen from
another infectious
agent into vaccinia virus were first described
in 1982

 peptides, which are only parts of an antigen,as
vaccines
 product is chemically defined, stable, and safe &
contains only important B-cell and T-cell
epitopes.

 Alternatively, a relatively small number of
plasmids, adsorbed to tiny beads, are blasted
through the skin by a “gene gun.”
 low cost, stability, and absence of infectivity
(although the immune response resembles that
seen after a natural infection)
 Potential disadvantages include integration of the
DNA into genome of the host cell, which might
result in transformation or tumorigenic events

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Vaccines: Types, Mechanisms and Uses